The overriding aim of this proposal is to investigate the therapeutic potential of blocking transforming growth factor-beta (TGF-beta) signaling for Alzheimer's disease. Terrence Town, Ph.D. is currently an NRSA/NIA post-doctoral fellow with the immediate goal of completing an additional year of mentored research. Dr. Town has been working at the interface of the immunology and neuroscience fields, and his current environment in Dr. Flavell's laboratory with co-sponsorship from Dr. Rakic positions him in the ideal environment within which to complete the mentored phase of the proposed project. Dr. Town's long-term goals inclulde establishing himself as an independent scientist in a tenure-track academic position, and contributing to understanding neuroimmune aspects of Alzheimer's disease, with the hope of finding novel therapeutic targets for this devastating illness. Dr. Town's career development plan includes receiving training and mentorship in neuroimmunology. Following the proposed one year period of mentored research, Dr. Town plans to make the transition to independence with the assistance of the proposed award. For the mentored period, Dr. Town proposes to evaluate Alzheimer-like pathology in a transgenic mouse model of the disease crossed with a transgenic mouse that has blocked TGF-beta signaling in innate immune cells. The proposed work during the mentored phase builds heavily on preliminary data that show that one such crossed mouse has mitigation of Alzheimer-like pathology. For the independent phase, Dr. Town will 1) investigate the potential cellular mechanism underlying reduced Alzheimer pathology in crossed mice, 2) adopt a pharmacotherapeutic approach by treating Alzheimer transgenic mice with TGF-beta receptor blocking antibody, and 3) conduct another mouse crossing experiment to determine if blocking TGF-beta signaling on innate immune cells mitigates Alzheimer-like pathology during its initial establishment or after active lesions are formed. RELEVANCE: Alzheimer's disease is the most common dementing illness in the United States, and it is estimated that over 3 million Americans over the age of 65 have the disease. This project aims to uncover a new avenue for the treatment of Alzheimer's disease by blocking a protein that has been shown to be involved in the pathological changes of the disease, specifically the brain's inflammatory response. [unreadable] [unreadable] [unreadable]